Mechanisms and relevance of apoptosis

  • J. Holtz
  • M. Tostlebe
  • D. Darmer


In recent years, we have witnessed an explosion in published research on apoptosis, the genetically predetermined intrinsic program of active cellular self destruction. Although this program of cell suicide originally was considered as highly ritualized and rather uniform, recent progress revealed an extreme variability in modifications of the program, with a plethora of molecules involved in induction, execution or inhibition of this program and with great differences in the program in different tissues. As in any organ of multicellular organisms, activation of the program contributes to the adjustment of cellular stoichiometry of the myocardium in mammals during embryogenesis [81], and it is more or less activated in all forms of postnatal cardiac pathologies [2, 4, 14, 29, 71, 82-84, 123, 160]. In spite of this abundance of published data on activated apoptosis in cardiomyocytes and in other cells of the heart, there is no consensus with regard to the importance of this cardiac apoptosis. Neither the relevance of the activated program for the progression of cardiac diseases, nor the therapeutic potential of anti-apoptotic interventions can be considered as established. Here, we will summarize our present view in this still controversial field together with some expectations on its future development.


Myocardial Apoptosis Apoptotic Program Myocyte Apoptosis Cell BioI Myocyte Loss 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Adams JM, Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281:1322–1325PubMedCrossRefGoogle Scholar
  2. 2.
    Anversa P, Kajstura J (1998) Myocyte cell death in the diseased heart. Circ Res 82:1231–1233PubMedCrossRefGoogle Scholar
  3. 3.
    Anversa P, Kajstura J (1998) Ventricular myocytes are not terminally differentiated in the adult mammalian heart. Circ Res 83:1–14PubMedCrossRefGoogle Scholar
  4. 4.
    Bartling B, Holtz J, Darmer D (1998) Contribution of myocyte apoptosis to myocardial infarction? Basic Res Cardiol 93:71–84PubMedCrossRefGoogle Scholar
  5. 5.
    Bartling B, Milting H, Schumann H, Darmer D, Arusoglu L, Koerner MM, El-Banayosy A, Koerfer R, Holtz J, Zerkowski HR (1999) Myocardial gene expression of regulators of myocyte apoptosis and myocyte calcium homeostasis during hemodynamic unloading by ventricular assist devices in patients with end-stage heart failure. Circulation 100 (suppl II):II216–II223PubMedGoogle Scholar
  6. 6.
    Baserga R, Hongo A, Rubini M, Prisco M, Valentinis B (1997) The IGF-I receptor in cell growth, transformation and apoptosis. Biochim Biophys Acta 1332:F105–F126PubMedGoogle Scholar
  7. 7.
    Bing OHL (1994) Hypothesis: apoptosis may be a mechanism for the transition to heart failure with chronic pressure overload. J Mol Cell Cardiol 26:943–948PubMedCrossRefGoogle Scholar
  8. 8.
    Black SC, Huang JQ, Rezaiefar P, Radinovic S, Eberhart A, Nicholson DW, Rodger IW (1998) Co-localization of the cysteine protease caspase-3 with apoptotic myocytes after in vivo myocardial ischemia and reperfusion in the rat. J Mol Cell Cardiol 30:733–742PubMedCrossRefGoogle Scholar
  9. 9.
    Boise TH, Thompson CB (1997) Bcl-xL, can inhibit apoptosis in cells that have undergone Fas-induced protease activation. Proc Natl Acad Sci 94:3759–3764PubMedCrossRefGoogle Scholar
  10. 10.
    Boldin MP, Varfolomeev EE, Pancer Z, Mett IL, Camonis JH, Wallach D (1995) A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain. J Biol Chem 270:7795–7798PubMedCrossRefGoogle Scholar
  11. 11.
    Bossy-Wetzel E, Green DR (1999) Caspases induce cytochrome c release from mitochondria by activating cytosolic factors. J Biol Chem 274:17484–17490PubMedCrossRefGoogle Scholar
  12. 12.
    Boveris A, Chance B (1973) The mitochondrial generation of hydrogen peroxide: general properties and effect of hyperbaric oxygen. Biochem J 134:707–716PubMedGoogle Scholar
  13. 13.
    Bozkurt B, Kribbs SB, Clubb FJ, Michael LH, Didenko VV, Hornsby PJ, Seta Y, Oral H, Spinale FG, Mann DL (1998) Pathophysiologically relevant concentrations of tumor necrosis factor-α promote progressive left ventricular dysfunction and remodeling in rats. Circulation 97:1382–1391PubMedCrossRefGoogle Scholar
  14. 14.
    Broemme HJ, Holtz J (1996) Apoptosis in the heart: when and why? Molecular and Cellular Biochemistry 163/164:261–275CrossRefGoogle Scholar
  15. 15.
    Brunet A, Bonni A, Zigmont MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–868PubMedCrossRefGoogle Scholar
  16. 16.
    Brustugun OT, Fladmark KE, Doskeland SO, Orrenius S, Zhivotovsky B (1998) Apoptosis induced by microinjection of cytochrome c is caspase-dependent and is inhibited by Bcl-2. Cell Death Differ 5:660–668PubMedCrossRefGoogle Scholar
  17. 17.
    Buja LM, Entman ML (1998) Modes of myocardial cell injury and cell death in ischemic heart disease. Circulation 98:1355–1357PubMedCrossRefGoogle Scholar
  18. 18.
    Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282:1318–1321PubMedCrossRefGoogle Scholar
  19. 19.
    Cascino I, Fiucci G, Papoff G, Ruberti G (1995) Three functional soluble forms of the human apoptosis-inducing Fas molecule are produced by alternative splicing. J Immunol 154:2706–2713PubMedGoogle Scholar
  20. 20.
    Cascino I, Papoff G, De Maria R, Testi R, Ruberti G (1996) Fas/Apo-1 (CD95) receptor lacking the intracytoplasmic signaling domain protects tumor cells from Fas-mediated apoptosis. J Immunol 156:13–17PubMedGoogle Scholar
  21. 21.
    Chance B, Sies H, Boveris A (1979) Hydroperoxide metabolism in mammalian organs. Physiol Rev 59:527–603PubMedGoogle Scholar
  22. 22.
    Cheng EHY, Kirsch DG, Clem RJ, Ravi R, Kastan MB, Bedi A, Ueno K, Hardwick JM (1997) Conversion of Bcl-2 to a Bax-like effector by caspases. Science 278:1966–1968PubMedCrossRefGoogle Scholar
  23. 23.
    Cheng W, Kajstura J, Nitahara JA, Li B, Reiss K, Liu Y, Clark WA, Krajewski S, Reed JC, Olivetti G, Anversa P (1996) Programmed myocyte cell death affects viable myocardium after infarction in rats. Exp Cell Res 226:316–327PubMedCrossRefGoogle Scholar
  24. 24.
    Cheng W, Li B, Kajstura J, Li P, Wolin MS, Sonnenblick EH, Hintze TH, Olivetti G, Anversa P (1995) Stretch induced programmed myocyte cell death. J Clin Invest 96:2247–2259PubMedCrossRefGoogle Scholar
  25. 25.
    Choi AM, Alam J (1996) Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury. Am J Respir Cell Mol Biol 15:9–19PubMedGoogle Scholar
  26. 26.
    Clem RJ, Cheng EHY, Karp CL, Kirsch DG, Ueno K, Takahashi A, Kastan MB, Griffin DE, Earnshaw WC, Veliuona MA, Hardwick JM (1998) Modulation of cell death by bcl-xL through caspase interaction. Proc Natl Acad Sci 95:554–559PubMedCrossRefGoogle Scholar
  27. 27.
    Cohen GM (1997) Caspases: the executioners of apoptosis. Biochem 326:1–16Google Scholar
  28. 28.
    Communal C, Singh K, Pimentel DR, Colucci WS (1998) Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the beta-adrenergic pathway. Circulation 98:1329–1334PubMedCrossRefGoogle Scholar
  29. 29.
    Cook SA, Poole-Wilson PA (1999) Cardiac myocyte apoptosis. Eur Heart J 28:1619–1629CrossRefGoogle Scholar
  30. 30.
    Cosulich SC, Worall V, Hege PJ, Grenn S, Clarke PR (1997) Regulation of apoptosis by BH3 domains in a cell-free system. Curr Biol 12:913–920CrossRefGoogle Scholar
  31. 31.
    Crook NE, Clem RJ, Miller LK (1993) An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif. J Virol 67:2168–2174PubMedGoogle Scholar
  32. 32.
    Cryns V, Yuan 1 (1998) Proteases to die for. Genes Dev 12:1551–1556PubMedCrossRefGoogle Scholar
  33. 33.
    Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231–241PubMedCrossRefGoogle Scholar
  34. 34.
    De Maria R, Zeuner A, Eramo A, Domenichelli C, Bonci D, Grignani F, Srinivasula SM, Alnemri ES, Testa U, Peschle C (1999) Negative regulation of erythropoiesis by caspase-mediated cleavage of GATA-1. Nature 401:489–493PubMedCrossRefGoogle Scholar
  35. 35.
    De Moissac D, Gurevich RM, Zheng H, Singal PK, Kirshenbaum LA (2000) Caspase activation and mitochondrial cytochrome C release during hypoxia-mediated apoptosis of adult ventricular myocytes [in process citation]. J Mol Cell Cardiol 32:53–63PubMedCrossRefGoogle Scholar
  36. 36.
    De Windt LJ, Lim HW, Taigen T, Wencker D, Condorelli G, Dorn GW 2nd, Kitsis RN, Molkentin JD (2000) Calcineurin-mediated hypertrophy protects cardiomyocytes from apoptosis in vitro and in vivo: an apoptosis-independent model of dilated heart failure. Circ Res 86:255–263PubMedCrossRefGoogle Scholar
  37. 37.
    del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G (1997) Interleukin-3- induced phosphorylation of BAD through the protein kinase Akt. Science 278:687–689PubMedCrossRefGoogle Scholar
  38. 38.
    Denecker G, Dooms H, Van Loo G, Vercammen D, Grooten J, Fiers W, Declercq W, Vandenabeele P (2000) Phosphatidyl serine exposure during apoptosis precedes release of cytochrome c and decrease in mitochondrial transmembrane potential. FEBS Lett 465:47–52PubMedCrossRefGoogle Scholar
  39. 39.
    Desagher S, Osen-Sand A, Nichols A, Eskes R, Montessuit S, Lauper S, Maundrell K, Antonsson B, Martinou JC (1999) Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis. J Cell Biol 144:891–901PubMedCrossRefGoogle Scholar
  40. 40.
    Deveraux QL, Takahashi R, Salvesen GS, Reed JC (1997) X-linked IAP is a direct inhibitor of cell-death proteases. Nature 388:300–304PubMedCrossRefGoogle Scholar
  41. 41.
    Didenko VV, Hornby PJ (1996) Presence of double-stranded breaks with single-base 3’ overhangs in cells undergoing apoptosis but not necrosis. J Cell Biol 135:1369–1376PubMedCrossRefGoogle Scholar
  42. 42.
    Dieterich S, Bieligk U, Beulich K, Hasenfuss G, Prestle J (2000) Gene expression of antioxidative enzymes in the human heart: increased expression of catalase in the end-stage failing heart. Circulation 101:33–39PubMedCrossRefGoogle Scholar
  43. 43.
    Diez J, Panizo A, Hernandez M, Vega F, Sola I, Fortuno MA, Pardo J (1997) Cardiomyocyte apoptosis and cardiac angiotensin-converting enzyme in spontaneously hypertensive rats. Hypertension 30:1029–1034PubMedCrossRefGoogle Scholar
  44. 44.
    Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM (1999) Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 399:601–605PubMedCrossRefGoogle Scholar
  45. 45.
    Dimmeler S, Haendeler J, Nehls M, Zeiher AM (1997) Suppression of apoptosis by nitric oxide via inhibition of interleukin-lfl-converting enzyme (ICE)-like and cysteine protease protein (CPP)-32-like proteases. J Exp Med 185:601–607PubMedCrossRefGoogle Scholar
  46. 46.
    Downward J (1998) Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin Cell Biol 10:262–267PubMedCrossRefGoogle Scholar
  47. 47.
    Duriez PJ, Shah GM (1997) Cleavage of poly(ADP-ribose) polymerase: a sensitive parameter to study cell death. Biochem Cell Biol 75:337–349PubMedCrossRefGoogle Scholar
  48. 48.
    Dutka DP, Elborn JS, Delamere F, Shale DJ, Morris GK (1993) Tumor necrosis factor a in severe congestive cardiac failure. Br Heart J 70:41–143CrossRefGoogle Scholar
  49. 49.
    Eisenstein RS, Garcia MD, Pettingell W, Munro HN (1991) Regulation of ferritin and heme oxygenase synthesis in rat fibroblasts by different forms of iron. Proc Natl Acad Sci 88:688–692PubMedCrossRefGoogle Scholar
  50. 50.
    Ekhterae D, Lin Z, Lundberg MS, Crow MT, Brosius FC 3rd, Nunez G (1999) ARC inhibits cytochrome c release from mitochondria and protects against hypoxia-induced apoptosis in heart-derived H9c2 cells. Circ Res 85:e70–77PubMedCrossRefGoogle Scholar
  51. 51.
    Elkon KB (1999) Caspases: multifunctional proteins. J Exp Med 190:1725–1727PubMedCrossRefGoogle Scholar
  52. 52.
    Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S (1998) A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391:43–50PubMedCrossRefGoogle Scholar
  53. 53.
    Engelhardt S, Hein L, Wiesmann F, Lohse MI (1999) Progressive hypertrophy and heart failure in betal-adrenergic receptor transgenic mice. Proc Natl Acad Sci 96:7059–7064PubMedCrossRefGoogle Scholar
  54. 54.
    Felzen B, Shilkrut M, Less H, Sarapov I, Maor G, Coleman R, Robinson RB, Berke G, Binah O (1998) Fas (CD95/Apo-1)-mediated damage to ventricular myocytes induced by cytotoxic T lymphocytes from perforin-deficient mice: a major role for inositol 1,4,5-triphosphate. Circ Res 82:438–450PubMedCrossRefGoogle Scholar
  55. 55.
    Ferris CD, Jaffrey SR, Sawa A, Takahashi M, Brady SD, Barrow RK, Tysoe SA, Wolosker H, Baranano DE, Doré S, Poss KD, Snyder SH (1999) Haem oxygenase-1 prevents cell death by regulating cellular iron. Nature Cell Biol 1:152–157PubMedCrossRefGoogle Scholar
  56. 56.
    Figulla HR, Rahlf G, Nieger M, Luig H, Kreuzer H (1985) Spontaneous hemodynamic improvement or stabilization and associated biopsy findings in patients with congestive cardiomyopathy. Circulation 71:1095–1104PubMedCrossRefGoogle Scholar
  57. 57.
    Finkel MS, Oddis CV, Jacob TD, Watkins SC, Hattler BG, Simmons RL (1992) Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 257:387–389PubMedCrossRefGoogle Scholar
  58. 58.
    Frantz S, Kobzik L, Kim YD, Fukazawa R, Medzhitov R, Lee RT, Kelly RA (1999) To114 (TLR4) expression in cardiac myocytes in normal and failing myocardium. J Clin Invest 104:271–280PubMedCrossRefGoogle Scholar
  59. 59.
    Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A, Sessa WC (1999) Regulation of endothelium-derived nitric oxide production by protein kinase Akt. Nature 399:597–601PubMedCrossRefGoogle Scholar
  60. 60.
    Gallitelli MF, Schultz M, Isenberg G, Rudolf F (1999) Twitch-potentiation increases calcium in peripheral more than in central mitochondria of guinea-pig ventricular myocytes. J Physiol 518:433–447PubMedCrossRefGoogle Scholar
  61. 61.
    Geng YJ, Ichikawa Y, Vatner DE, Wagner TE, Bishop SP, Vatner SF, Homcy CJ (1999) Apoptosis of cardiac myocytes in Gsalpha transgenic mice. Circ Res 84:34–42PubMedCrossRefGoogle Scholar
  62. 62.
    Goetz RM, Holtz J (1999) Enhanced angiotensin-converting enzyme activity and impaired endothelium-dependent vasodilation in aortae from hypertensive rats: evidence for a causal link. Clin Sci 97:165–174PubMedCrossRefGoogle Scholar
  63. 63.
    Green DR, Reed JC (1998) Mitochondria and apoptosis. Science 281:1309–1312PubMedCrossRefGoogle Scholar
  64. 64.
    Gregory T, Yu C, Ma A, Orkin SH, Blobel GA, Weiss MJ (1999) GATA-1 and erythropoietin cooperate to promote erythroid cell survival by regulating bcl-xL expression. Blood 94:87–96PubMedGoogle Scholar
  65. 65.
    Gross A, Yin XM, Wang K, Wei MC, Jockel J, Milliman C, Erdjument-Bromage H, Tempst P, Korsmeyer SJ (1999) Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-XL prevents this release but not tumor necrosis-Rl/Fas death. J Biol Chem 274:1156–1163PubMedCrossRefGoogle Scholar
  66. 66.
    Guerra S, Leri A, Wang X, Finato N, Di Loreto C, Beltrami CA, Kajstura J, Anversa P (1999) Myocyte death in the failing human heart is gender dependent. Circ Res 85:856–866PubMedCrossRefGoogle Scholar
  67. 67.
    Haider N, Kharbanda S, Chandrasekar Y, Srinivasula SM, Fitzpatrick JM, Anand I, Alnemri ES, Narula J (1999) Caspase-3 mediated cleavage of troponin-C at evolutionarily conserved calcium binding site: relevance of apoptosis in heart failure (abstr). Circulation 100 (suppl):I-283Google Scholar
  68. 68.
    Halenbeck R, MacDonald H, Roulston A, Chen TT, Conroy L, Williams LT (1998) CPAN, a human nuclease regulated by the caspase-sensitive inhibitor DFF45. Current Biol 8:537–540CrossRefGoogle Scholar
  69. 69.
    Hamet P, Richard L, Dam TV, Teiger E, Orlov SN, Gaboury L, Gossard F, Tremblay J (1995) Apoptosis in target organs of hypertension. Hypertension 26:642–648PubMedCrossRefGoogle Scholar
  70. 70.
    Harada H, Becknell B, Wilm M, Mann M, Huang LJ, Taylor SS, Scott JD, Korsmeyer SJ (1999) Phosphorylation and inactivation of BAD by mitochondria-anchored protein-kinase A. Mol Cell 3:413–422PubMedCrossRefGoogle Scholar
  71. 71.
    Haunstetter A, Izumo S (1998) Apoptosis: basic mechanisms and implications for cardiovascular disease. Circ Res 82:1111–1129PubMedCrossRefGoogle Scholar
  72. 72.
    Haunstetter A, Izumo S (2000) Toward antiapoptosis as a new treatment modality. Circ Res 86:371–376PubMedCrossRefGoogle Scholar
  73. 73.
    Hirota H, Chen J, Betz U, Rajewsky K, Gu Y, Ross JJ, Muller W, Chien KR (1999) Loss of gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress. Cell 97:189–198PubMedCrossRefGoogle Scholar
  74. 74.
    Holtz J, Darmer D (2000) Death Receptors and Their Ligands. Kluwer Academic Publisher, pp 5–28Google Scholar
  75. 75.
    Ide T, Tsutsui H, Kinugawa S, Suematsu N, Hayashidani S, Ichikawa K, Utsumi H, Machida Y, Egashira K, Takeshita A (2000) Direct evidence for increased hydroxyl radicals originating from superoxide in the failing myocardium. Circ Res 86:152–157PubMedCrossRefGoogle Scholar
  76. 76.
    Ide T, Tsutsui H, Kinugawa S, Utsumi H, Kang D, Hattori N, Uchida K, Arimura K, Egashira K, Takeshita A (1999) Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circ Res 85:357–363PubMedCrossRefGoogle Scholar
  77. 77.
    Iwai-Kanai E, Hasegawa K, Araki M, Kakita T, Morimoto T, Sasayama S (1999) Alpha-and beta-adrenergic pathways differentially regulate cell type-specific apoptosis in rat cardiac myocytes. Circulation 100:305–311PubMedCrossRefGoogle Scholar
  78. 78.
    Iwase M, Bishop SP, Uechi M, Vatner DE, Shannon RP, Kudej RK, Wight DC, Wagner TE, Ishikawa Y, Homcy CJ, Vatner SF (1996) Adverse effects of chronic endogenous sympathetic drive induced by cardiac GS alpha overexpression. Circ Res 78:517–524PubMedCrossRefGoogle Scholar
  79. 79.
    Iwase M, Uechi M, Vatner DE, Asai K, Shannon RP, Kudej RK, Wagner TE, Wight DC, Patrick TA, Ishikawa Y, Homcy CJ, Vatner SF (1997) Cardiomyopathy induced by cardiac Gs alpha overexpression. Am J Physiol 272:H585–H589PubMedGoogle Scholar
  80. 80.
    Jaattela M, Wissing D, Kokholm K, Kallunki T, Egeblad M (1998) Hsp70 exerts its anti-apoptotic function downstream of caspase-3-like proteases. EMBO J 17:6124–6134PubMedCrossRefGoogle Scholar
  81. 81.
    James TN (1994) Normal and abnormal consequences of apoptosis in the human heart from postnatal morphogenesis to paroxysmal arrhythmias. Circulation 90:556–573PubMedCrossRefGoogle Scholar
  82. 82.
    James TN (1997) Apoptosis in congenital heart disease. Coronary Art Dis 8:599–616CrossRefGoogle Scholar
  83. 83.
    James TN (1997) Complex causes of fatal myocardial infarction. Circulation 96:1696–1700PubMedCrossRefGoogle Scholar
  84. 84.
    James TN, Terasaki F, Pavlovich ER, Vikhert AM (1993) Apoptosis and pleomorphic mitochondriosis in the sinus nodes surgically excised from five patients with long QT syndrome. J Lab Clin Med 122:309–323PubMedGoogle Scholar
  85. 85.
    Janssen PML, Lehnart SE, Prestle J, Hasenfuss G (1999) Preservation of contractile characteristics of human myocardium in multi-day culture. J Mol Cell Cardiol 31:1419–1427PubMedCrossRefGoogle Scholar
  86. 86.
    Janssen PML, Hasenfuss G, Zeitz O, Lehnart S, Darmer D, Holtz J, Schumann H (1999) Afterload-induced apoptosis in multicellular myocardial preparations in functional culture (abstr). Circulation 100(suppl):I-758Google Scholar
  87. 87.
    Janssen PML, Lehnart SE, Prestle J, Lynker JC, Salfeld P, Just H, Hasenfuss G (1998) The trabecula culture system: a novel technique to study contractile parameters over a multiday period. Am J Physiol 274:H1481–H1488PubMedGoogle Scholar
  88. 88.
    Jarreta D, Orus J, Barrietos A, Miro O, Roig E, Heras M, Moraes CT, Cardellach F, Casedemont J (2000) Mitochondrial function in heart muscle from patients with idiopathic dilated cardiomyopathy. Cardiovasc Res 45:860–865PubMedCrossRefGoogle Scholar
  89. 89.
    Kajstura J, Leri A, Finato N, Di Loreto C, Beltrami CA, Anversa P (1998) Myocyte proliferation in end-stage cardiac failure in humans. Proc Natl Acad Sci 95:8801–8805PubMedCrossRefGoogle Scholar
  90. 90.
    Kan H, Xie Z, Finkel MS (1999) TNF-alpha enhances cardiac myocyte NO production through MAP kinase-mediated NF-kappaB activation. Am J Physiol 277:H1641–1646PubMedGoogle Scholar
  91. 91.
    Kanoh M, Takemura G, Misao J, Hayakawa Y, Aoyama T, Nishigaki K, Noda T, Fujiwara T, Fukuda F, Minatoguchi S, Fujiwara H (1999) Significance of myocytes with positive DNA in situ nick end-labeling (TUNEL) in hearts with dilated cardiomyopathy: not apoptosis but DNA repair. Circulation 99:2757–2764PubMedCrossRefGoogle Scholar
  92. 92.
    Kerr PM, Suleiman MS, Halestrap AP (1999) Reversal of permeability transition during recovery of hearts from ischemia and its enhancement by pyruvate. Am J Physiol 276:H496–H502PubMedGoogle Scholar
  93. 93.
    Keyse SM, Tyrrell RM (1989) Heme oxygenase is the major 32-kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite. Proc Natl Acad Sci 86:99–103PubMedCrossRefGoogle Scholar
  94. 94.
    Kitada S, Krajewska M, Zhang X, Scudiero D, Zapata JM, Wang HG, Shabaik A, Tudor G, Krajewski S, Myers TG, Johnson GS, Sausville EA, Reed JC (1998) Expression and location of pro-apoptotic bc1–2 family protein BAD in normal human tissues and tumor cell lines. Am J Pathol 152:51–61PubMedGoogle Scholar
  95. 95.
    Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD (1997) The release of cytochrome c from mitochondria: a primary site for bcl-2 regulation of apoptosis. Science 275:1132–1136PubMedCrossRefGoogle Scholar
  96. 96.
    Kluck RM, Martin SJ, Hoffman BM, Zhou JS, Green DR, Newmeyer DD (1997) Cytochrome c activation of CPP32-like proteolysis plays a critical role in a Xenopus cell-free apoptosis system. Embo J 16:4639–4649PubMedCrossRefGoogle Scholar
  97. 97.
    Knudsen CM, Tung CS, Tourtelotte WG, Brown GA, Korsmeyer SJ (1995) Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science 270:96–99CrossRefGoogle Scholar
  98. 98.
    Kops GJPL, De Ruiter ND, De Vries-Smits AMM, Powell DR, Bos JL, Burgering BMT (1999) Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature 398:630–634PubMedCrossRefGoogle Scholar
  99. 99.
    Koseki T, Inohara N, Chen S, Nunez G (1998) ARC, an inhibitor of apoptosis expressed in skeletal muscle and heart that interacts selectively with caspases. Proc Natl Acad Sci 95:5156–5160PubMedCrossRefGoogle Scholar
  100. 100.
    Kroemer G, Dallaporta B, Resche-Rigon M (1998) The mitochondrial death/life regulator in apoptosis and necrosis. Ann Rev Physiol 60:619–642CrossRefGoogle Scholar
  101. 101.
    Krown KA, Page MT, Nguyen C, Zechner D, Gutierrez V, Comstock KL, Glembotski CC, Quintana PJE, Sabbadini RA (1996) Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes - Involvement of the sphingolipid signaling cascade in cardiac cell death. J Clin Invest 98:2854–2865PubMedCrossRefGoogle Scholar
  102. 102.
    Kubota T, McTiernan CF, Frye CS, Demetris AJ, Feldman AM (1997) Cardiac-specific overexpression of tumor necrosis factor-alpha causes lethal myocarditis in transgenic mice. J Card Fail 3:117–124PubMedCrossRefGoogle Scholar
  103. 103.
    Kubota T, McTiernan CF, Frye CS, Slawson SE, Lemster BH, Koretsky AP, Demetris AJ, Feldman AM (1997) Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha. Circ Res 81:627–635PubMedCrossRefGoogle Scholar
  104. 104.
    Kuwana T, Smith JJ, Muzio M, Dixit V, Newmeyer DD, Kornbluth S (1998) Apoptosis induction by caspase-8 is amplified through the mitochondrial release cytochrome c. J Biol Chem 273:16589–16594PubMedCrossRefGoogle Scholar
  105. 105.
    Lavoie JN, Nguyen M, Marcellus RC, Branton BE, Shore GC (1998) E4orf4, a novel adenovirus death factor that induces p53-independent apoptosis by a pathway that is not inhibited by zVAD-fmk. J Cell Biol 140:637–645PubMedCrossRefGoogle Scholar
  106. 106.
    Leri A, Claudio PP, Li Q, Wang X, Reiss K, Wang S, Malhotra A, Kajstura J, An-versa P (1998) Stretch-mediated release of angiotensin II induces myocyte apoptosis by activating p53 that enhances the local renin-angiotensin system and decreases the bcl-2-to-bax ratio in the cell. J Clin Invest 101:1326–1342PubMedCrossRefGoogle Scholar
  107. 107.
    Leri A, Liu Y, Claudio PP, Kajstura J, Wang X, Wang S, Kang P, Malhotra A, An-versa P (1999) Insulin-like growth factor-1 induces Mdm2 and downregulates p53, attenuating the myocyte renin-angiotensin system and stretch-mediated apoptosis. Am J Pathol 154:567–580PubMedCrossRefGoogle Scholar
  108. 108.
    Levine B, Kalman J, Mayer L, Fillit HM, Packer M (1990) Elevated circulation levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 323:236–241PubMedCrossRefGoogle Scholar
  109. 109.
    Levkau B, Scatena M, Giachelli CM, Ross R, Raines EW (1999) Apoptosis overrides survival signals through a caspase-mediated dominant-negative NF-KB loop. Nature Cell Biol 1:227–233PubMedCrossRefGoogle Scholar
  110. 110.
    Li H, Zhu H, Xu CJ, Yuan J (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94:491–501PubMedCrossRefGoogle Scholar
  111. 111.
    Li J, Billiar TR, Talanian RV, Kim YM (1997) Nitric oxide reversibly inhibits seven members of the caspase family via S-nitrosylation. Biochem Biophys Res Comm 240:419–424PubMedCrossRefGoogle Scholar
  112. 112.
    Li Q, Li B, Wang X, Levi A, Jana KP, Liu X, Kajstura J, Baserga R, Anversa P (1997) Overexpression of insulin growth factor-1 in mice protects from myocyte death after infarction, attenuating ventricular dilation, wall stress and cardiac hypertrophy. J Clin Invest 100:1991–1999PubMedCrossRefGoogle Scholar
  113. 113.
    Li ZH, Bing OHL, Long XL, Robinson KG, Lakatta EG (1997) Increased cardiocyte apoptosis during the transition to heart failure in the spontaneously hypertensive rat. Am J Heart 272:H2313–H2319Google Scholar
  114. 114.
    Liao R, Gwathmey JK, Wang CK (1999) A possible mechanism for decreased myocardial contractility in idiopathic dilated cardiomyopathy: significance of spatial relationship between Helix A and Ca2+-binding loop II in human cardiac troponin C (abstr). Circulation 100 (suppl):II-60Google Scholar
  115. 115.
    Lindenmayer GE, Harigaya S, Bajusz E, Schwartz A (1970) Oxidative phosphorylation and calcium transport of mitochondria isolated from cardiomyopathic hamster hearts. J Mol Cell Cardiol 9:249–259CrossRefGoogle Scholar
  116. 116.
    Lindenmayer GE, Sordahl LA, Harigaya S, Allen JC, Besch HR, Schwartz A (1971) Some biochemical studies on subcellular systems isolated from fresh recipient human cardiac tissue obtained during transplantation. Am J Cardiol 27:277–283PubMedCrossRefGoogle Scholar
  117. 117.
    Liu X, Kim CN, Yang J, Jemmerson R, Wang X (1996) Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 86:147–157PubMedCrossRefGoogle Scholar
  118. 118.
    Liu X, Li P, Widlack P, Zuo H, Luo X, Garrard WT, Wang X (1998) The 40-kDa subunit of DNA fragmentation factor induces DNA fragmentation and chromatin condensation during apoptosis. Proc Natl Acad Sci 95:8461–8466PubMedCrossRefGoogle Scholar
  119. 119.
    Liu X, Zou H, Slaughter C, Wang X (1997) DFF, a heterodimeric protein that functions downstream of caspase 3 to trigger DNA fragmentation during apoptosis. Cell 89:175–184PubMedCrossRefGoogle Scholar
  120. 120.
    Lorenzo HK, Susin SA, Penninger J, Kroemer G (1999) Apoptosis inducing factor (AIF): a phylogenetically old, caspase-independent effector of cell death. Cell Death Differ 6:516–524PubMedCrossRefGoogle Scholar
  121. 121.
    Lotem J, Kama R, Sachs L (1999) Suppression or induction of apoptosis by opposing pathways downstream from calcium-activated calcineurin. Proc Natl Acad Sci USA 96:12016–12020PubMedCrossRefGoogle Scholar
  122. 122.
    Luo X, Budihardjo I, Zou H, Slaughter C, Wang X (1998) Bid, a Bcl-2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94:481–490PubMedCrossRefGoogle Scholar
  123. 123.
    MacLellan WR, Schneider MD (1997) Death by design: programmed cell death in cardiovascular biology and disease. Circ Res 81:137–144PubMedCrossRefGoogle Scholar
  124. 124.
    Maines MD (1997) The heme oxygenase system: a regulator of second messenger gases. Ann Rev Pharmacol Toxicol 37:517–554CrossRefGoogle Scholar
  125. 125.
    Malhotra R, Brosius FC (1999) Glucose uptake and glycolysis reduce hypoxia-induced apoptosis in cultured neonatal rat cardiac myocytes. J Biol Chem 274:12567–12575PubMedCrossRefGoogle Scholar
  126. 126.
    Mannick JB, Hausladen A, Liu LM, Hess DT, Zeng M, Miao QX, Kane LS, Gow AJ, Stamler JS (1999) Fas-induced caspase denitrosylation. Science 284:651–654PubMedCrossRefGoogle Scholar
  127. 127.
    Mannick JB, Miao XQ, Stamler JS (1997) Nitric oxide inhibits Fas-induced apoptosis. J Biol Chem 272:24125–24128PubMedCrossRefGoogle Scholar
  128. 128.
    Martinou I, Desagher S, Eskes R, Antonsson B, Andre E, Fakan S, Martinou JC (1999) The release of cytochrome c from mitochondria during apoptosis of NGF-deprived sympathetic neurons is a reversible event. J Cell Biol 144:883–889PubMedCrossRefGoogle Scholar
  129. 129.
    Marzo I, Susin SA, Petit PX, Ravagnan L (1998) Caspases disrupt mitochondrial membrane barrier function. FEBS Lett 427:198–202PubMedCrossRefGoogle Scholar
  130. 130.
    Maulik N, Engelman DT, Watanabe M, Engelman RM, Das DK (1996) Nitric oxide - a retrograde messenger for carbon monoxide signaling in ischemic heart. Mol Cell Biochem 157:75–86PubMedCrossRefGoogle Scholar
  131. 131.
    Maulik N, Engelman DT, Watanabe M, Engelman RM, Rousou JA, Flack JE, Deaton DW, Gorbunov NV, Elsayed NM, Kagan VE, Das DK (1996) Nitric oxide/carbon monoxide: a molecular switch for myocardial preservation during ischemia. Circulation 94:II-398-II-406Google Scholar
  132. 132.
    Maulik N, Sharma HS, Das DK (1996) Induction of the haem oxygenase gene expression during the reperfusion of ischemic rat myocardium. J Mol Cell Cardiol 28:1261–1270PubMedCrossRefGoogle Scholar
  133. 133.
    Maurer I, Zierz S (1993) Myocardial respiratory chain enzyme activities in idiopathic dilated cardiomyopathy, and comparison with those in atherosclerotic coronary artery disease and valvular aortic stenosis. Am J Cardiol 72:428–433PubMedCrossRefGoogle Scholar
  134. 134.
    McCarthy NJ, Whyte MKB, Gilbert CS, Evan GI (1997) Inhibition of Ced-3/ICErelated proteases does not prevent cell death induced by oncogenes, DNA damage, or the Bc1–2 homologue Bak. J Cell Biol 136:215–227PubMedCrossRefGoogle Scholar
  135. 135.
    McCord JM (1998) Iron, free radicals, and oxidative injury. Semin Hematol 35:5–12PubMedGoogle Scholar
  136. 136.
    Melkonyan HS, Chang WC, Shapiro JP, Mahadevappa M, Fitzpatrick PA, Kiefer MC, Tomei LD, Umansky SR (1997) SARPs: a family of secreted apoptosis-related proteins. Proc Natl Acad Sci 94:13636–13641PubMedCrossRefGoogle Scholar
  137. 137.
    Mestril R, Dillmann WH (1991) Heat shock and adaptive response to ischemia. Trends Cardiovasc Med 1:240–244PubMedCrossRefGoogle Scholar
  138. 138.
    Mestril R, Dillmann WH (1995) Heat shock proteins and protection against myocardial ischemia. J Mol Cell Cardiol 27:45–52PubMedCrossRefGoogle Scholar
  139. 139.
    Molketin JD, Lu JR, Antos CL, Markham B, Richardson J, Robbins J, Grant SR, Olson EN (1998) A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93:215–228CrossRefGoogle Scholar
  140. 140.
    Morawietz H, Rohrbach S, Darmer D, Hakim K, Zerkowski HR, Holtz J-B (1996) Angiotensin converting enzyme inhibitor treatment upregulates the expression of endothelial nitric oxide synthase in human atrial myocardium (abstr). Circulation 94 (suppl I):1–521Google Scholar
  141. 141.
    Mosser DD, Caron AW, Bourget L, Denis-Larose C, Massie B (1997) Role of the human heat shock protein hsp70 in protection against stress-induced apoptosis. Mol Cell Biol 17:5317–5327PubMedGoogle Scholar
  142. 142.
    Mukae N, Enari M, Sakahira H, Fukuda Y, Inazawa J, Toh H, Nagata S (1998) Molecular cloning and characterization of human caspase-activated DNase. Proc Natl Acad Sci 95:9123–9128PubMedCrossRefGoogle Scholar
  143. 143.
    Muller SP, Pregla R, Holtz J (1998) Anti-apoptotic action of insulin-like growth factor I (IGF-I) in myocardium of rats with hypertension due to inhibition of nitric oxide synthase (abstr). Naunyn-Schmiedeberg’s Arch Pharmacol 358 (suppl 3):94Google Scholar
  144. 144.
    Miiller-Werdan U, Schumann H, Fuchs R, Reithmann C, Loppnow H, Koch S, Zimny-Arndt U, He C, Darmer D, Jungblut P, Stadler J, Holtz J, Werdan K (1997) Tumor-necrosis factor a (TNFa) is cardiodepressant in pathophysiologically relevant concentrations without inducing inducible nitric oxide-(NO)synthase (iNOS) or triggering serious cytotoxity. J Mol Cell Cardiol 29:2915–2923CrossRefGoogle Scholar
  145. 145.
    Muller-Werdan U, Schumann H, Loppnow H, Fuchs R, Darmer D, Stadler J, Holtz J, Werdan K (1998) Endotoxin and tumor necrosis factor a exert a similar proinflammatory effect in neonatal rat cardiomyocytes, but have different cardiodepressant profiles. J Mol Cell Cardiol 30:1027–1036PubMedCrossRefGoogle Scholar
  146. 146.
    Musaro A, McCullagh KJ, Naya FJ, Olson EN, Rosenthal N (1999) IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATcl. Nature 400:581–585PubMedCrossRefGoogle Scholar
  147. 147.
    Narula J, Haider N, Virmani R, DiSalvo T, Kolodgie FD, Hajjar RJ, Schmidt U, Semigran MJ, Dec W, Khaw BA (1996) Apoptosis in myocytes in end-stage heart failure. N Engl J Med 335:1182–1189PubMedCrossRefGoogle Scholar
  148. 148.
    Narula J, Pandey P, Arbustini E, Haider N, Narula N, Kolodgie FD, Dal Bello B, Semigran MJ, Bielsa-Madeu A, Dec GW, Israels S, Ballester M, Virmani R, Saxena S, Kharbanda S (1999) Apoptosis in heart failure: release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy. Proc Natl Acad Sci 96:8144–8149PubMedCrossRefGoogle Scholar
  149. 149.
    Neubauer S, Horn M, Cramer M, Harre K, Newell JB, Peters W, Pabst T, Ertl G, Hahn D, Ingwall JS, Kochsiek K (1997) Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation 96:2190–2196PubMedCrossRefGoogle Scholar
  150. 150.
    Neubauer S, Remkes H, Spindler M, Horn M, Wiesmann F, Prestle J, Walzel B, Ertl G, Hasenfuss G, Wallimann T (1999) Downregulation of the Na(+)-creatine cotransporter in failing human myocardium and in experimental heart failure. Circulation 100:1847–1850PubMedCrossRefGoogle Scholar
  151. 151.
    Nicholson DW, Thornberry NA (1997) Caspases: killer proteases. Trends Biochem Sci 22:299–306PubMedCrossRefGoogle Scholar
  152. 152.
    Nicotera P, Leist P (1997) Energy supply and the shape of death in neurons and lymphoid cells. Cell Death Diff 4:435–442CrossRefGoogle Scholar
  153. 153.
    Nishigaki K, Minatoguchi S, Seishima M, Asano K, Noda T, Yasuda N, Sano H, Kumada H, Takemura M, Noma A, Tanaka T, Watanabe S, Fujiwara H (1997) Plasma Fas ligand, an inducer of apoptosis, and plasma soluble Fas, an inhibitor of apoptosis, in patients with chronic congestive heart failure. JACC 29:1214–1220PubMedGoogle Scholar
  154. 154.
    Nunez G, Benedict MA, Hu Y, Inohara N (1998) Caspases: the proteases of the apoptotic pathway. Oncogene 17:3237–345PubMedCrossRefGoogle Scholar
  155. 155.
    Nunez G, del Peso L (1998) Linking extracellular survival signals and the apoptotic machinery. Curr Opin Neurobiol 8:613–618PubMedCrossRefGoogle Scholar
  156. 156.
    Okamura T, Miura T, Takemura G, Fujiwara H, Iwamoto H, Kawamura S, Kimura M, Ikeda Y, Iwatate M, Matsuzaki M (2000) Effect of caspase inhibitors on myocardial infarct size and myocyte DNA fragmentation on the ischemic-reperfused rat heart. Cardiovasc Res 45:642–650PubMedCrossRefGoogle Scholar
  157. 157.
    Olivetti G, Abbi R, Quaini F, Kajstura I, Cheng W, Nitahara JA, Quaini E, DiLoreto C, Beltrami CA, Krajewski S, Reed JC, Anversa P (1997) Apoptosis in the failing human heart. N Engl J Med 336:1131–1141PubMedCrossRefGoogle Scholar
  158. 158.
    Olivetti G, Quaini F, Sala R, Lagrasta C, Corradi D, Bonacina E, Gambert SR, Cigola E, Anversa P (1996) Acute myocardial infarction in humans is associated with activation of programmed myocyte cell death in the surviving portion of the heart. J Mol Cell Cardiol 28:2005–2016PubMedCrossRefGoogle Scholar
  159. 159.
    Orkin SH, Weiss MJ (1999) Apoptosis: cutting red-cell production. Nature 401:433–436PubMedCrossRefGoogle Scholar
  160. 160.
    O’Rourke B (1999) Apoptosis: rekindling the mitochondrial fire. Circ Res 85:880–883PubMedCrossRefGoogle Scholar
  161. 161.
    Orth K, Chinnaiyan AM, Garg M, Froelich CJ, Dixit VM (1996) The CED-3/ICElike protease Mch2 is activated during apoptosis and cleaves the death substrate lamin A. J Biol Chem 271:16443–16446PubMedCrossRefGoogle Scholar
  162. 162.
    Oskarsson HJ, Coppey L, Weiss RM, Li WG (2000) Antioxidants attenuate myocyte apoptosis in the remote non-infarcted myocardium following large myocardial infarction. Cardiovasc Res 45:679–687PubMedCrossRefGoogle Scholar
  163. 163.
    Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner MB (1999) NF-KB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401:82–85PubMedCrossRefGoogle Scholar
  164. 164.
    Papoff G, Cascino I, Eramo A, Starace G, Lynch DH, Ruberti G (1996) An N-terminal domain shared by Fas/Apo-1 (CD95) soluble variants prevents cell death in vitro. J Immunol 156:4622–4630PubMedGoogle Scholar
  165. 165.
    Paradis P, Dali-Youcef N, Paradis FW, Thibault G, Nemer M (2000) Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling. Proc Natl Acad Sci 97:931–936PubMedCrossRefGoogle Scholar
  166. 166.
    Patterson SD, Spahr CS, Daugas E, Susin SA, Irinopoulou T, Koehler C, Kroemer G (2000) Mass spectrometric identification of proteins released from mitochondria undergoing permeability transition. Cell Death Differ 7:137–144PubMedCrossRefGoogle Scholar
  167. 167.
    Pawlowski J, Kraft AS (2000) Bax-induced apoptotic cell death. Proc Natl Acad Sci USA 97:529–531PubMedCrossRefGoogle Scholar
  168. 168.
    Piot CA, Padmanaban D, Ursell PC, Sievers RE, Wolfe CL (1997) Ischaemic preconditioning decreases apoptosis in rat hearts in vivo. Circulation 96:1598–1604PubMedCrossRefGoogle Scholar
  169. 169.
    Poss KD, Tonegawa S (1997) Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci 94:10919–10924PubMedCrossRefGoogle Scholar
  170. 170.
    Poss KD, Tonegawa S (1997) Reduced stress defense in heme oxygenase 1-deficient cells. Proc Natl Acad Sci 94:10925–10930PubMedCrossRefGoogle Scholar
  171. 171.
    Raczniak TJ, Chesney CF, Allen JR (1977) Oxidative phosphorylation and respiration by mitochondria from normal, hypertrophied and failing rat hearts. J Mol Cell Cardiol 9:215–223PubMedCrossRefGoogle Scholar
  172. 172.
    Reed JC (1994) Mini-review: cellular mechanisms of disease series: bcl-2 and the regulation of programmed cell death. J Cell Biol 124:1–6PubMedCrossRefGoogle Scholar
  173. 173.
    Reed JC (1997) Double identity for proteins of the Bcl-2 family. Nature 387:773–776PubMedCrossRefGoogle Scholar
  174. 174.
    Reed JC, Paternostro G (1999) Postmitochondrial regulation of apoptosis during heart failure. Proc Natl Acad Sci 96:7614–7616PubMedCrossRefGoogle Scholar
  175. 175.
    Rohrbach S, Yan X, Weinberg E, Hasan F, Bartunek J, Marchionni MA, Lorell BH (1999) Neuregulin in cardiac hypertrophy in rats with aortic stenosis: differential expression of erbB2 and erbB4 receptors. Circulation 100:407–412PubMedCrossRefGoogle Scholar
  176. 176.
    Romashkova JA, Makarov SS (1999) NF-KB is a target of AKT in anti-apoptotic PDGF signalling. Nature 401:86–90PubMedCrossRefGoogle Scholar
  177. 177.
    Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC (1997) The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. Embo J 16:6914–6925PubMedCrossRefGoogle Scholar
  178. 178.
    Sabbah HN, Sharov V, Riddle JM, Kono T, Lesch M, Goldstein S (1992) Mitochondria) abnormalities in myocardium of dogs with chronic heart failure. J Mol Cell Cardiol 24:1333–1347PubMedCrossRefGoogle Scholar
  179. 179.
    Sahara S, Aoto M, Eguchi Y, Imamoto N, Yoneda Y, Tsujimoto Y (1999) Acinus is a caspase-3-activated protein required for apoptotic chromatin condensation. Nature 401:168–173PubMedCrossRefGoogle Scholar
  180. 180.
    Sakahira H, Enari M, Nagata S (1998) Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis. Nature 391:96–99PubMedCrossRefGoogle Scholar
  181. 181.
    Samali A, Zhivotovsky B, Jones DP, Orrenius S (1998) Detection of pro-caspase-3 in cytosol and mitochondria of various tissues. FEBS Lett 431:167–169PubMedCrossRefGoogle Scholar
  182. 182.
    Saraste A, Pulkki K, Kallajoki M, Heikkila P, Laine P, Mattila S, Nieminen MS, Parvinen M, Voipio-Pulkki LM (1999) Cardiomyocyte apoptosis and progression of heart failure to transplantation. Eur J Clin Invest 29:380–386PubMedCrossRefGoogle Scholar
  183. 183.
    Saraste A, Pulkki K, Kallajoki M, Henriksen K, Parvinen M, Voipio-Pulkki LM (1997) Apoptosis in human acute myocardial infarction. Circulation 95:320–323PubMedCrossRefGoogle Scholar
  184. 184.
    Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH, Peter ME (1998) Two CD95 (APO-1/Fas) signaling pathways. EMBO J 17:1675–1687PubMedCrossRefGoogle Scholar
  185. 185.
    Schaper J, Froede R, Hein S, Buck A, Hashizume H, Speiser B, Briedl A, Bleese N (1991) Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy. Circulation 83:504–514PubMedCrossRefGoogle Scholar
  186. 186.
    Schaper J, Lorenz-Meyer S, Suzuki K (1999) The role of apoptosis in dilated cardiomyopathy. Herz 24:219–224PubMedCrossRefGoogle Scholar
  187. 187.
    Scheid MP, Duronio V (1998) Dissociation of cytokine-induced phosphorylation of BAD and activation of PKB/akt: involvement of MEK upstream of BAD phosphorylation. Proc Natl Acad Sci 95:7439–7444PubMedCrossRefGoogle Scholar
  188. 188.
    Schellenberger E, Szibor M, Holtz J (2000) In vivo imaging of apoptosis in overload-induced heart failure: potential approaches and application implications. Z Kardiol (in press)Google Scholar
  189. 189.
    Schumann H, Holtz J, Zerkowski HR, Hatzfeld M (2000) Expression of secreted frizzled related proteins 3 and 4 in human ventricular myocardium correlates with apoptosis related gene expression. Cardiovasc Res 45:720–728PubMedCrossRefGoogle Scholar
  190. 190.
    Schumann H, Morawietz H, Hakim K, Zerkowski HR, Eschenhagen T, Holtz J, Darmer D (1997) Alternative splicing of the primary Fas transcript generating soluble Fas antagonists is suppressed in the failing human ventricular myocardium. Biochem Biophys Res Comm 239:794–798PubMedCrossRefGoogle Scholar
  191. 191.
    Schwartz SM (1998) Cell death and the caspase cascade. Circulation 97:227–229PubMedCrossRefGoogle Scholar
  192. 192.
    Schwarz F, Schaper J, Kittstein D, Flameng W, Walter P, Schaper W (1981) Reduced volume fraction of myofibrils in myocardium of patients with decompensated pressure overload. Circulation 63:1299–1304PubMedCrossRefGoogle Scholar
  193. 193.
    Semsarian C, Wu MJ, Ju YK, Marciniec T, Yeoh T, Allen DG, Harvey RP, Graham RM (1999) Skeletal muscle hypertrophy is mediated by a Ca2+-dependent calcineurin signalling pathway. Nature 400:576–581PubMedCrossRefGoogle Scholar
  194. 194.
    Seta Y, Shan K, Bozkurt B, Oral H, Mann DL (1996) Basic mechanisms in heart failure: the cytokine hypothesis. J Cardiac Failure 2:243–249CrossRefGoogle Scholar
  195. 195.
    Sharma HS, Maulik N, Gho BCG, Das DK, Verdouw PD (1996) Coordinated expression of heme oxygenase-1 and ubiquitin in the porcine heart subjected to ischemia and reperfusion. Mol Cell Biochem 157:111–116PubMedCrossRefGoogle Scholar
  196. 196.
    Singh K, Communal C, Sawyer DB, Colucci WS (2000) Adrenergic regulation of myocardial apoptosis. Cardiovasc Res 45:713–719PubMedCrossRefGoogle Scholar
  197. 197.
    Skulachev VP (1996) Role of uncoupled and non-coupled oxidations in maintenance of safely low levels of oxygen and its one-electron reductants. Quart Rev Biophys 29:169–202CrossRefGoogle Scholar
  198. 198.
    Soares MP, Lin Y, Anrather J, Csizmadia E, Takigami K, Sato K, Grey ST, Colvin RB, Choi AM, Poss KD, Bach FH (1998) Expression of heme oxygenase-1 can determine cardiac xenograft survival. Nature Med 4:1073–1077PubMedCrossRefGoogle Scholar
  199. 199.
    Srinivasula SM, Ahmad M, Fernandes-Alnemri T, Alnemri ES (1998) Autoactivation of procaspase-9 by Apaf-l-mediated oligomerization. Mol Cell 1:949–957PubMedCrossRefGoogle Scholar
  200. 200.
    Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN (1987) Bilirubin is an antioxidant of physiological importance. Science 235:1043–1046PubMedCrossRefGoogle Scholar
  201. 201.
    Stone JR, Marletta MA (1994) Soluble guanylate cyclase from bovine lung: activation by nitric oxide and carbon monoxide and spectral characterization of the ferrous and ferric states. Biochemistry 33:36–40Google Scholar
  202. 202.
    Stroh C, Schulze-Osthoff K (1998) Death by a thousand cuts: an ever increasing list of caspase substrates. Cell Death Diff 5:997–1000CrossRefGoogle Scholar
  203. 203.
    Susin SA, Lorenzo HK, Zamzami N, Marzo I, Brenner C, Larochette N, Prévost MC, Alzari PM, Kroemer G (1999) Mitochondrial release of caspase-2 and -9 during the apoptotic process. J Exp Med 189:381–393PubMedCrossRefGoogle Scholar
  204. 204.
    Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodletti DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397:441–446PubMedCrossRefGoogle Scholar
  205. 205.
    Taigen T, De Windt LJ, Lim HW, Molketin JD (2000) Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophy. Proc Natl Acad Sci 97:1196–1201PubMedCrossRefGoogle Scholar
  206. 206.
    Takahashi A, Alnemri ES, Lazebnik YA, Fernandes-Alnemri T, Litwack G, Moir RD, Goldman RD, Poirier GG, Kaufmann SH, Earnshaw WC (1996) Cleavage of lamin A by Mch2α but not CPP32: multiple interleukin 1β-converting enzyme-related proteases with distinct substrate recognition properties are active in apoptosis. Proc Natl Acad Sci 93:8395–8400PubMedCrossRefGoogle Scholar
  207. 207.
    Takemoto M, Egashira K, Usui M, Numaguchi K, Tomita H, Tsutsui H, Shimokawa H, Sueishi K, Takeshita A (1997) Important role of tissue angiotensin-converting enzyme activity in the pathogenesis of coronary vascular and myocardial structural changes induced by long-term blockade of nitric oxide synthesis in rats. J Clin Invest 99:278–287PubMedCrossRefGoogle Scholar
  208. 208.
    Tanaka M, Ito H, Adachi S, Akimoto H, Nishikawa T, Kasajima T, Marumo F, Hiroe M (1994) Hypoxia induces apoptosis with enhanced expression of Fas antigen messenger RNA in cultured neonatal rat cardiomyocytes. Circ Res 75:426–433PubMedCrossRefGoogle Scholar
  209. 209.
    Teiger E, Dam TV, Richard L, Wisnewsky C, Tea BS, Gaboury L, Tremblay J, Schwartz K, Hamet P (1996) Apoptosis in pressure overload-induced heart hyper-trophy in the rat. J Clin Invest 97:2891–2897PubMedCrossRefGoogle Scholar
  210. 210.
    Tewari M, Dixit VM (1995) Fas-and tumor necrosis factor-induced apoptosis is inhibited by the pox virus crmA gene product. J Biol Chem 270:3255–3260PubMedCrossRefGoogle Scholar
  211. 211.
    Thornberry NA, Lazebnik Y (1998) Caspases: enemies within. Science 281:1313–1316CrossRefGoogle Scholar
  212. 212.
    Torre-Amione G, Bozkurt B, Deswal A, Mann DL (1999) An overview of tumor necrosis factor α and the failing human heart. Curr Opin Cardiol 14:206–210PubMedCrossRefGoogle Scholar
  213. 213.
    Torre-Amione G, Kapadia S, Benedict C, Oral H, Young JB, Mann DL (1996) Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol 27:1201–1206PubMedCrossRefGoogle Scholar
  214. 214.
    Torre-Amione G, Kapadia S, Lee J, Bies RD, Lebovitz R, Mann DL (1995) Expression and functional significance of tumor necrosis factor receptors in human myocardium. Circulation 92:1487–1493PubMedCrossRefGoogle Scholar
  215. 215.
    Torre-Amione G, Stetson SJ, Youker KA, Durand JB, Radovancevic B, Delgado RM, Frazier OH, Entman ML, Noon GP (1999) Decreased expression of tumor necrosis factor-alpha in failing human myocardium after mechanical circulatory support: a potential mechanism for cardiac recovery. Circulation 100:1189–1193PubMedCrossRefGoogle Scholar
  216. 216.
    Torriglia A, Perani P, Brossas JY, Chaudun E, Treton J, Courtois Y, Counis MF (1998) L-DNase II, a molecule that links proteases and endonucleases in apoptosis, derives from the ubiquitous serpin leukocyte elastase inhibitor [published erratum appears in Mol Cell Biol 1998 Aug; 18(8):4947]. Mol Cell Biol 18:36123–619Google Scholar
  217. 217.
    Trost SU, Omens JH, Karlon WJ, Meyer M, Mestril R, Covell JW, Dillmann WH (1998) Protection against myocardial dysfunction after a brief ischemic period in transgenic mice expressing inducible heat shock protein 70. J Clin Invest 101:855–862PubMedCrossRefGoogle Scholar
  218. 218.
    Tsujimoto Y (1997) Apoptosis and necrosis: intracellular ATP levels as a determinant for cell death modes. Cell Death Diff 4:429–434CrossRefGoogle Scholar
  219. 219.
    Tsujimoto Y (1998) Role of Bc1–2 family proteins in apoptosis: apoptosomes or mitochondria? Genes to Cells 3:697–707PubMedCrossRefGoogle Scholar
  220. 220.
    Tsujimoto Y, Shimizu S (2000) Bcl-2 family: life-or-death switch. FEBS Lett 466:6–10PubMedCrossRefGoogle Scholar
  221. 221.
    Vancompernolle K, Van Herreweghe F, Pynaert G, Van de Craen M, De Vos K, Totty N, Sterling A, Fiers W, Vandenbeele P, Grooten J (1998) Atractyloside-induced release of cathepsin B, a protease with caspase-processing activity. FEBS Lett 438:150–158PubMedCrossRefGoogle Scholar
  222. 222.
    Van der Heiden MG, Chandel NS, Williamson EK, Schumacker PT, Thompson CB (1997) Bcl-xL regulates the membrane potential and volume homeostasis of mitochondria. Cell 91:627–637CrossRefGoogle Scholar
  223. 223.
    Van der Heiden MG, Thompson CB (1999) Bcl-2 proteins: regulators of apoptosis or of mitochondrial homeostasis? Nature Cell Biol 1:E209–E216CrossRefGoogle Scholar
  224. 224.
    Villa P, Kaufmann SH, Earnshaw WC (1997) Caspases and caspases inhibitors. TIBS 22:388–393PubMedGoogle Scholar
  225. 225.
    Villani G, Greco M, Papa S, Attardi G (1998) Low reserve of cytochrome c oxidase capacity in vivo in the respiratory chain of a variety of human cell types. J Biol Chem 273:31829–31836PubMedCrossRefGoogle Scholar
  226. 226.
    Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS (1998) NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 281:1680–1683PubMedCrossRefGoogle Scholar
  227. 227.
    Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, McKeon F, Bobo T, Franke TF, Reed JC (1999) Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science 284:339–343PubMedCrossRefGoogle Scholar
  228. 228.
    Wang HG, Rapp UR, Reed JC (1996) Bcl-2 targets the protein kinase Raf-1 to mitochondria. Cell 87:629–638PubMedCrossRefGoogle Scholar
  229. 229.
    Wickman A, Isgaard J, Adams MA, Friberg P (1997) Inhibition of nitric oxide in rats. Regulation of cardiovascular structure and expression of insulin-like growth factor I and its receptor messenger RNA. J Hypertens 15:751–759PubMedCrossRefGoogle Scholar
  230. 230.
    Wolf V, Ke G, Dharmarajan AM, Bielke W, Artuso L, Saurer S, Friis R (1997) DDC-4, an apoptosis-associated gene, is a secreted frizzled relative. FEBS Lett 417:385–389PubMedCrossRefGoogle Scholar
  231. 231.
    Wollert KC, Heineke J, Westermann J, Ludde M, Fiedler B, Zierhut W, Laurent D, Bauer MK, Schulze-Osthoff K, Drexler H (2000) The cardiac fas (APO-1/CD95) receptor/Fas ligand system: relation to diastolic wall stress in volume-overload hypertrophy in vivo and activation of the transcription factor AP-1 in cardiac myocytes. Circulation 101:1172–1178PubMedCrossRefGoogle Scholar
  232. 232.
    Wu CF, Bishopric NH, Pratt RE (1997) Atrial natriuretic peptide induces apoptosis in neonatal rat cardiac myocytes. J Biol Chem 272:14860–14866PubMedCrossRefGoogle Scholar
  233. 233.
    Wyllie AH, Kerr JFR, Currie AR (1980) Cell death: the significance of apoptosis. Int Rev Cytol 68:251–306PubMedCrossRefGoogle Scholar
  234. 234.
    Yamaguchi S, Yamaoka M, Okuyama M, Nitoube J, Fukui A, Shirakabe M, Shirakawa K, Nakamura N, Tomoike H (1999) Elevated circulating levels and cardiac secretion of soluble Fas ligand in patients with congestive heart failure. Am J Cardiol 83:1500–1503PubMedCrossRefGoogle Scholar
  235. 235.
    Yamamoto S, Sawada K, Shimomura H, Kawamura K, James TN (2000) On the nature of cell death during remodeling of hypertrophied human myocardium. J Mol Cell Cardiol 32:161–175PubMedCrossRefGoogle Scholar
  236. 236.
    Yaoita H, Ogawa K, Maehara K, Maruyama Y (1998) Attenuation of ischemia/reperfusion injury in rats by a caspase inhibitor. Circulation 97:276–281PubMedCrossRefGoogle Scholar
  237. 237.
    Zamzami N, Susin SA, Marchetti P, Hirsch T, I G-M, Castedo M, Kroemer G (1996) Mitochondrial control of nuclear apoptosis. J Exp Med 183:1533–1544PubMedCrossRefGoogle Scholar
  238. 238.
    Zechner D, Craig R, Hanford DS, McDonough PM, Sabbadini RA, Glembotsky CC (1998) MKK6 activates myocardial cell NF-KB and inhibits apoptosis in a p38 mitogen-activated protein kinase dependent manner. J Biol Chem 273:8232–8239PubMedCrossRefGoogle Scholar
  239. 239.
    Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14–3–3 not BCL-X. Cell 87:619–628PubMedCrossRefGoogle Scholar
  240. 240.
    Zhivotovsky B, Orrenius S, Brugustun OT, Doskeland SO (1998) Injected cytochrome c induces apoptosis. Nature 391:449–450PubMedCrossRefGoogle Scholar
  241. 241.
    Zoratti M, Szabo I (1995) The mitochondrial permeability transition. Biochim Biophys Acta 1241:139–176PubMedCrossRefGoogle Scholar
  242. 242.
    Zou H, Henzel WJ, Liu X, Lutschg A, Wang X (1997) Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 90:405–413PubMedCrossRefGoogle Scholar
  243. 243.
    Zou H, Li Y, Liu X, Wang X (1999) An APAF-1 cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem 274:11549–11556PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2000

Authors and Affiliations

  • J. Holtz
    • 1
  • M. Tostlebe
    • 1
  • D. Darmer
    • 1
  1. 1.Institute of PathophysiologyHalleGermany

Personalised recommendations